Safety, immunogenicity, and antibody persistence following an investigational Streptococcus pneumoniae and Haemophilus influenzae triple-protein vaccine in a phase 1 randomized controlled study in healthy adults.

We investigated a protein-based nontypeable Haemophilus influenzae (NTHi) and pneumococcal (HiP) vaccine containing pneumococcal histidine triad D (PhtD), detoxified pneumolysin (dPly), and NTHi protein D (PD) in adults. In a phase I study, 40 healthy 18- to 40-year-old subjects were randomized (2:2:1) to receive two HiP doses administered 60 days apart, with or without AS03 adjuvant (HiP-AS and HiP groups, respectively), or Engerix B (GlaxoSmithKline, Belgium) as a control. Safety, antibodies, and antigen-specific CD4(+) T-cell immune responses were assessed before and until 480 days after vaccination. No serious adverse events were reported, and no subject withdrew due to an adverse event. Local and systemic symptoms were reported more frequently in the HiP-AS group than in the other two groups. The frequency and intensity of local and systemic symptoms appeared to increase after the second dose of HiP-AS or HiP but not Engerix B. Antibody geometric mean concentrations (GMCs) for PhtD, dPly, and PD increased after each dose of HiP-AS or HiP, with higher GMCs being observed in the HiP-AS group (statistically significant for anti-PD after dose 1 and anti-Ply after dose 2). GMCs remained higher at day 420 than prior to vaccination in both the HiP-AS and HiP groups. Antigen-specific CD4(+) T cells increased after each dose but were unmeasurable by day 480. Two doses of an investigational PhtD-dPly-PD protein vaccine induced humoral immunity and antigen-specific CD4(+) T-cell responses after each dose, with generally higher responses when the vaccine was administered with AS03. HiP combined with AS03 appeared to be more reactogenic than the antigens alone. (This study has been registered at ClinicalTrials.gov under registration no. NCT00814489.).

Prelicensure evaluation of combination vaccines.

There is considerable public health interest in licensing safe and effective combination vaccines. Because combination vaccines may progress rapidly from phase 1 to a pivotal phase 2 immunogenicity trial, a rigorous approach to address product issues early in development is warranted. Clinical studies to evaluate the safety, immunogenicity, and (when necessary) clinical end point efficacy of combination vaccines should be randomized and well controlled in most cases. A large phase 3 safety study (i.e., a study that enrolls thousands of vaccinees) should be included in the development plan if a phase 3 (clinical end point) efficacy trial will not be conducted. Often, the new combination vaccine under development contains immunogens that have all been previously licensed, have demonstrated efficacy in earlier clinical trials, or both. For such products, comparative immunogenicity data may be sufficient to support efficacy. When applicable, clinical data to support simultaneous administration with other relevant vaccines should be obtained. Given the complexity of combination vaccine development, early consultation with United States Food and Drug Administration can be invaluable.

Perspectives on the manufacture of combination vaccines.

Evolving regulatory requirements in the United States and Europe create major challenges for manufacturers tasked with production of vaccines that contain > or =9 separate antigens capable of protecting against infectious diseases, such as diphtheria, tetanus, pertussis, polio, hepatitis B, and Haemophilus influenza b, in a single shot. This article describes 10 steps that can facilitate the process of licensing these complex vaccines. It also points out problems associated with the use of animal tests for the crucial step of potency testing for batch release caused by the inherent variability of such tests and the difficulties of interpreting their results.

Perspectives on the state of combination vaccines: summary of the rapporteur for the International Symposium on Combination Vaccines.

Recent advances in immunology, biotechnology, and other sciences now give the prospect of a wide variety of new vaccines that can bring further improvements in health but that pose some theoretical issues relating to safety and efficacy, as well as practical issues relating to logistics, number of injections, and other factors. Combination vaccines are essential if society is to take full advantage of new vaccines that can further reduce the burden of infectious diseases in this country and around the world. The major issues relating to combination vaccines are much the same today as those discussed at a 1993 meeting. However, considerable progress has been made in developing solutions to the problems, and prospects are good that many of these issues will be resolved in the next 2-3 years.

Making vaccines more acceptable--methods to prevent and minimize pain and other common adverse events associated with vaccines.

The growing abundance of highly immunogenic vaccines has arrived with a burden of pain, distress, and common adverse reactions that in turn may interfere with parental compliance and aggravate anti-vaccine sentiment. In a study of 150 children in each of 2 age-groups, we found that approximately 20% of the subjects suffered serious distress or worse. During the procedural phase, approximately 90% of the 15-to-18 month old children and 45% of the 4-to-6 year old children showed serious distress or worse. To address non-adherence with pediatric vaccine schedules, we must consider all of the possible issues that might prevent a parent from taking a child to a health care provider for vaccination. In that same study we identified useful predictors for both preparatory and procedural distress - predictors that might be used in identifying children who might benefit from preventive interventions. Vaccine providers might consider a variety of interventions. Attitude, empathy, instruction, and practice have all been shown to have a salutatory effect upon pain and anxiety with medical procedures in general and specifically with vaccinations. Distraction has also been found to be an effective method for distress and pain prevention in children. More formal methods of clinical hypnosis which combine a deep state of relaxation with focused imagery and suggestion have also been found to be effective in helping children and adolescents prepare for, cope with, and tolerate the pain and anxiety associated with medical procedures. So-called 'sugar nipples' delivering small amounts of sucrose orally at the time of a painful procedure in an infant has been not been shown to decrease vaccination pain and studies on refrigerant topical anesthetics are mixed. Studies have found a eutectic mixture of 2.5% lidocaine and 2.5% prilocaine (EMLA) effective in providing adequate local anesthesia in children, but it suffers from problems in practical application. Studies with various injection techniques have not identified ready solutions, and although jet injection appears to provoke less anxiety and cause less immediate pain, studies also indicate a somewhat greater incidence of delayed local reactogenicity including soreness and edema. Other measures to prevent or rapidly treat other common adverse events have been shown effective and should be considered as well.

Current status and future trends in vaccine regulation--USA.

In regulating vaccines, the US Food and Drug Administration (FDA) is governed by the Code of Federal Regulations. These regulations serve as the framework for product characterization, as well as preclinical and clinical testing strategies. Novel vaccine approaches such as combination vaccines, vectored vaccines, new adjuvants, and novel delivery systems pose unique regulatory challenges for the FDA. If US licensure is sought, communication with the FDA throughout the clinical development of a product is essential to identify and implement the appropriate strategies for demonstrating the safety and effectiveness of a new product.

Booster vaccination against diphtheria and tetanus in man. Comparison of three different vaccine formulations--III.

Adverse reactions and antibody levels were compared following a booster vaccination of 177 Danish military recruits with a plain, an aluminium hydroxide (0.5 mg Al per human dose, HD) and a calcium phosphate (0.25 mg Ca per HD) adsorbed diphtheria-tetanus (D-T) vaccine. The calcium phosphate adsorbed vaccine was given in a HD of 3 Lf of D and T toxoids and proved to be of equal efficacy as the aluminium hydroxide adsorbed vaccine which was injected in a dose containing twice the antigen amount. The calcium phosphate vaccine caused fewer adverse reactions than the one adsorbed to aluminium hydroxide. The plain vaccine (6 Lf per HD of D and T toxoid) had the highest efficacy with a similar low occurrence of adverse reactions as the calcium phosphate adsorbed vaccine. Potency assays in mice were in accordance with these immunogenicity results in man if a two dose immunization schedule was followed, but not if the vaccines were compared after a single immunization as requested by the procedure for potency testing according to current WHO and European Pharmacopoeia requirements. Both of the adsorbed vaccines primed mice for specific IgE antibody formation. This could be detected after a second immunization with either of the adsorbed vaccines or with the plain D-T vaccine. Also in humans, immunization with the plain vaccine boosted specific IgE formation to a detectable level. This may be ascribed to adjuvant priming during the primary vaccination series some 20 years previously.

Booster vaccination against diphtheria and tetanus in man. Comparison of calcium phosphate and aluminium hydroxide as adjuvants--II.

Diphtheria and tetanus antibody levels were measured before and four weeks after booster vaccination of 313 Danish military recruits participating in a clinical trial to compare aluminium hydroxide and calcium phosphate as adjuvants in diphtheria-tetanus vaccines (DT). Twenty-eight percent of the men had a diphtheria pre-vaccination content below a protective level of 0.01 IU ml-1. The calcium phosphate adsorbed vaccine showed the highest efficacy for both antigens. Adverse reactions were rare but more frequent in the calcium group than in the aluminium group. No correlation was found between pre- or post-vaccination levels and adverse reactions and both vaccines gave rise to specific IgE formation. The results show that calcium phosphate is more effective but not a safer alternative to aluminium hydroxide when compared in vaccines containing 1.0 mg ml-1 of Ca or of Al.

Oral immunization against diphtheria and tetanus infections by fluid diphtheria and tetanus toxoids.

Purified diphtheria toxoid incorporated in egg yolk and mixed with a medicinal plant seed was used to orally immunize rabbits against diphtheria infection. Animals were partially immunized against a lethal diphtheria toxin challenge. The immunity was complete when gastric enzyme juices were inhibited before oral vaccination by aprotinin, a natural protease inhibitor. Rabbits and monkeys were orally immunized against both diphtheria and tetanus in the same way by pre-treatment with aprotinin. Adult volunteers receiving protease inhibitor before administration of oral toxoids have shown a significant rise in specific circulating antitoxins.

[Combined (associated) vaccination against quarantinable infections]. / Kompleksnaia (assotsiirovannaia) vaktsinatsiia protiv karantinnykh infektsii.

The presence of several active foci of infection of different etiology is an indication for complex (combined) immunization against these diseases. The scheme of complex (combined) immunization against plague, cholera and yellow fever has been experimentally substantiated and successfully tested on volunteers.

[Combined (associated) immunization against typhoid, typhus and plague]. / Kompleksnaia (assotsiirovannaia) immunizatsiia protiv briushnogo i sypnogo tifov i chumy.

The article substantiates epidemiological expediency of complex (associated) immunization of servicemen and population against typhoid, typhus and plague in polyetiological zones of these infections, and also in cases of simultaneous proliferation of these diseases. For simultaneous preventive vaccination against these infections a complex immunization scheme was experimentally substantiated and clinically approved. It is based on national commercial vaccines and ensures a simultaneous administration of 2-3 vaccine preparations by hypodermic syringe or jet injection. Typhoid and typhus vaccines are injected under one shoulder-blade, and plague vaccine is injected under another shoulder-blade. This complex vaccine is harmless, moderately reactogenic, develops expressing immunity which have the same protective features as monovaccines alone. This scheme is recommended for use in anti-epidemic practice.

[A system for the mass combined vaccination of the adult population against influenza, viral hepatitis, typhoid, meningitis and diphtheria]. / Sistema massovoi kompleksnoi vaktsinatsii vzroslogo naselennia protiv grippa, virusnogo gepatita, briushnogo tifa, meningita i difterii.

A safe, moderately reactogenic and immunologically effective scheme of complex (combined) immunization against meningitis A, diphtheria, typhoid fever, viral hepatitis A and influenza has been developed as the result of experimental and clinico-immunological studies. Depending on the epidemiological situation, the newly developed scheme can be used in two variants. According to the first variant of this scheme, the following preparations are injected subcutaneously into three different sites: a mixture of group A meningococcal vaccine and diphtheria toxoid, typhoid vaccine and influenza vaccine. The second variant of the scheme differs from its first variant in using intramuscular injection of normal human immunoglobulin instead of injection of influenza vaccine. Moreover, in practical realization these variants may be altered by excluding vaccines, unnecessary under present conditions. The newly developed scheme of vaccinal prophylaxis is recommended for practical use.